Sridevi Krishnan

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• Nguyen, M. T., Krishnan, S., Phatak, S. V., & Karakas, S. E. (2023). Anti-Mullerian Hormone-Based Phenotyping Identifies Subgroups of Women with Polycystic Ovary Syndrome with Differing Clinical and Biochemical Characteristics. Diagnostics (Basel, Switzerland), 13(3).
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  Even though polycystic ovary syndrome (PCOS) was originally defined as "amenorrhea associated with bilateral polycystic ovaries", women without PCO morphology can be included in this diagnosis. This may contribute to the clinical heterogeneity seen in PCOS. Serum anti-Mullerian hormone (AMH) correlates with the number of ovarian cysts. We investigated whether phenotyping based on serum AMH can distinguish subgroups of PCOS with different clinical and biochemical characteristics. The electronic medical records of 108 women with PCOS (Rotterdam criteria) were reviewed. The serum AMH value correlated inversely (0.03 < < 0.0001) with age, weight, and BMI values and directly with serum total testosterone (T), free T, and bioavailable T values. When divided into quartiles based on serum AMH values, the women in the highest quartile (AMH: 18.5 ± 9.9 ng/mL; n = 27) had lower BMI (29.4 ± 6.9 vs. 34.0 ± 10.6-36.7 ± 7.2 kg/m) but higher total T (51.3 ± 27.2 vs. 26.5 ± 10.4-35.1 ± 16.3 ng/dL), free T (7.7 ± 6.0 vs. 4.4 ± 2.3-5.7 ± 3.2 ng/dL), and bioavailable T (22.1 ± 17.0 vs. 12.2 ± 6.6-16.5 ± 8.7 ng/dL) values. The combination of high AMH and high testosterone values may point to the ovaries and reproductive etiology for PCOS in this subgroup. Thus, AMH-based phenotyping may provide a practical and cost-effective tool to explore the heterogeneity in PCOS.
• Zhang, Y., Krishnan, S., Bao, B., Chiang, A. W., Sorrentino, J. T., Schinn, S. M., Kellman, B. P., & Lewis, N. E. (2023). Preparing glycomics data for robust statistical analysis with GlyCompareCT. STAR protocols, 4(2), 102162.
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  GlyCompareCT is a portable command-line tool to facilitate downstream glycomic data analyses, by addressing data inherent sparsity and non-independence. Inputting glycan abundances, users can run GlyCompareCT with one line of code to obtain the abundances of a minimal substructure set, named glycomotif, thereby quantifying hidden biosynthetic relationships between measured glycans. Optional parameters tuning and annotation are supported for personal preference. For complete details on the use and execution of this protocol, please refer to Bao et al. (2021)..
• Krishnan, S., Freytag, T., Jiang, X., Schuster, G. U., Woodhouse, L. R., Keim, N. L., & Stephensen, C. B. (2022). Effect of a diet based on the dietary guidelines for americans on inflammation markers in women at risk for cardiometabolic disease: results of a randomized, controlled trial. BMC nutrition, 8(1), 157.
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  To evaluate the effect of a diet pattern based on Dietary Guidelines for Americans (DGA), in a controlled feeding setting, on plasma markers of inflammation and on cytokine production by peripheral blood mononuclear cells (PBMC).
• Krishnan, S., Gertz, E. R., Adams, S. H., Newman, J. W., Pedersen, T. L., Keim, N. L., & Bennett, B. J. (2022). Effects of a diet based on the Dietary Guidelines on vascular health and TMAO in women with cardiometabolic risk factors. Nutrition, metabolism, and cardiovascular diseases : NMCD, 32(1), 210-219.
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  Recent evidence links trimethylamine oxide (TMAO) to endothelial dysfunction, an early indicator of cardiovascular disease. We aimed to determine whether short-term consumption of a diet patterned after the 2010 Dietary Guidelines for Americans (DGA) would affect endothelial function, plasma TMAO concentrations, and cardiovascular disease risk, differently than a typical American Diet (TAD).
• Krishnan, S., O'Connor, L., Wang, Y., Gertz, E., Campbell, W., & Bennett, B. (2022). Adopting a Mediterranean-style eating pattern with low, but not moderate, unprocessed, lean red meat intake reduces fasting serum trimethylamine N-oxide (TMAO) in adults who are overweight or obese. British Journal of Nutrition, 128(9). doi:10.1017/S0007114521004694
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  A Mediterranean-style eating pattern (MED-EP) may include moderate red meat intake. However, it is unknown if the pro-atherogenic metabolite trimethylamine N-oxide (TMAO) is affected by the amount of red meat consumed with a MED-EP. The results presented are from a secondary, retrospective objective of an investigator-blinded, randomised, crossover, controlled feeding trial (two 5-week interventions separated by a 4-week washout) to determine if a MED-EP with 200 g unprocessed lean red meat/week (MED-CONTROL) reduces circulating TMAO concentrations compared to a MED-EP with 500 g unprocessed lean red meat/week (MED-RED). Participants were seventy-seven women and twelve men (n 39 total) who were either overweight or obese (BMI: mean (30·5) (sem 0·3) kg/m2). Serum samples were obtained following an overnight fast both before (pre) and after (post) each intervention. Fasting serum TMAO, choline, carnitine and betaine concentrations were measured using a targeted liquid chromatography-MS. Data were analysed to assess if (a) TMAO and related metabolites differed by intervention and (b) if changes in TMAO were associated with changes in Framingham 10-year risk score. Serum TMAO was lower post-intervention following MED-CONTROL compared with MED-RED intervention (post-MED-CONTROL 3·1 (sem 0·2) m v. post-MED-RED 5·0 (sem 0·5) m, P < 0·001), and decreased following MED-CONTROL (pre- v. post-MED-CONTROL, P = 0·025). Exploratory analysis using mixed model ANCOVA identified a positive association between changes in TMAO and changes in homoeostatic model assessment of insulin resistance (P = 0·036). These results suggest that lower amounts of red meat intake lead to lower TMAO concentrations in the context of a MED-EP.
• Newman, J. W., Krishnan, S., Borkowski, K., Adams, S. H., Stephensen, C. B., & Keim, N. L. (2022). Assessing Insulin Sensitivity and Postprandial Triglyceridemic Response Phenotypes With a Mixed Macronutrient Tolerance Test. Frontiers in nutrition, 9, 877696.
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  The use of meal challenge tests to assess postprandial responses in carbohydrate and fat metabolism is well established in clinical nutrition research. However, challenge meal compositions and protocols remain a variable. Here, we validated a mixed macronutrient tolerance test (MMTT), containing 56-g palm oil, 59-g sucrose, and 26-g egg white protein for the parallel determination of insulin sensitivity and postprandial triglyceridemia in clinically healthy subjects. The MMTT was administered in two study populations. In one, women with overweight/obese BMIs ( = 43) involved in an 8-week dietary intervention were administered oral glucose tolerance tests (OGTTs) and MMTTs within 2 days of each other after 0, 2, and 8 weeks of the dietary intervention. In the other, 340 men and women between 18 and 64 years of age, with BMI from 18-40 kg/m, completed the MMTT as part of a broad nutritional phenotyping effort. Postprandial blood collected at 0, 0.5, 3, and 6 h was used to measure glucose, insulin, and clinical lipid panels. The MMTT postprandial insulin-dependent glucose disposal was evaluated by using the Matsuda Index algorithm and the 0- and 3 h blood insulin and glucose measures. The resulting MMTT insulin sensitivity index (ISI) was strongly correlated ( = 0.77, < 0.001) with the OGTT-dependent 2 h composite Matsuda index (ISI), being related by the following equation: Log (ISI) = [0.8751 x Log(ISI)] -0.2115. An area under the triglyceride excursion curve >11.15 mg/mL h calculated from the 0, 3, and 6 h blood draws established mild-to-moderate triglyceridemia in agreement with ∼20% greater prevalence of hypertriglyceridemia than fasting indications. We also demonstrated that the product of the 0 to 3 h and 3 to 6 h triglyceride rate of change as a function of the triglyceride incremental area under the curve optimally stratified subjects by postprandial response patterns. Notably, ∼2% of the population showed minimal triglyceride appearance by 6 h, while ∼25% had increasing triglycerides through 6 h. Ultimately, using three blood draws, the MMTT allowed for the simultaneous determination of insulin sensitivity and postprandial triglyceridemia in individuals without clinically diagnosed disease.
• Richardson, C. E., Krishnan, S., Gray, I. J., Keim, N. L., & Newman, J. W. (2022). The Omega-3 Index Response to an 8 Week Randomized Intervention Containing Three Fatty Fish Meals Per Week Is Influenced by Adiposity in Overweight to Obese Women. Frontiers in nutrition, 9, 810003.
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  The Dietary Guidelines for Americans (DGA) recommends consuming ~225 g/wk of a variety of seafood providing >1.75 g/wk of long-chain omega-3 fatty acids to reduce cardiovascular disease risk, however individual responses to treatment vary.
• Tacad, D. K., Tovar, A. P., Richardson, C. E., Horn, W. F., Keim, N. L., Krishnan, G. P., & Krishnan, S. (2022). Satiety Associated with Calorie Restriction and Time-Restricted Feeding: Central Neuroendocrine Integration. Advances in nutrition (Bethesda, Md.), 13(3), 758-791.
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  This review focuses on summarizing current knowledge on how time-restricted feeding (TRF) and continuous caloric restriction (CR) affect central neuroendocrine systems involved in regulating satiety. Several interconnected regions of the hypothalamus, brainstem, and cortical areas of the brain are involved in the regulation of satiety. Following CR and TRF, the increase in hunger and reduction in satiety signals of the melanocortin system [neuropeptide Y (NPY), proopiomelanocortin (POMC), and agouti-related peptide (AgRP)] appear similar between CR and TRF protocols, as do the dopaminergic responses in the mesocorticolimbic circuit. However, ghrelin and leptin signaling via the melanocortin system appears to improve energy balance signals and reduce hyperphagia following TRF, which has not been reported in CR. In addition to satiety systems, CR and TRF also influence circadian rhythms. CR influences the suprachiasmatic nucleus (SCN) or the primary circadian clock as seen by increased clock gene expression. In contrast, TRF appears to affect both the SCN and the peripheral clocks, as seen by phasic changes in the non-SCN (potentially the elusive food entrainable oscillator) and metabolic clocks. The peripheral clocks are influenced by the primary circadian clock but are also entrained by food timing, sleep timing, and other lifestyle parameters, which can supersede the metabolic processes that are regulated by the primary circadian clock. Taken together, TRF influences hunger/satiety, energy balance systems, and circadian rhythms, suggesting a role for adherence to CR in the long run if implemented using the TRF approach. However, these suggestions are based on only a few studies, and future investigations that use standardized protocols for the evaluation of the effect of these diet patterns (time, duration, meal composition, sufficiently powered) are necessary to verify these preliminary observations.
• Tacad, D. K., Tovar, A. P., Richardson, C. E., Horn, W. F., Krishnan, G. P., Keim, N. L., & Krishnan, S. (2022). Satiety Associated with Calorie Restriction and Time-Restricted Feeding: Peripheral Hormones. Advances in nutrition (Bethesda, Md.), 13(3), 792-820.
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  Calorie restriction (CR) is a common approach to inducing negative energy balance. Recently, time-restricted feeding (TRF), which involves consuming food within specific time windows during a 24-h day, has become popular owing to its relative ease of practice and potential to aid in achieving and maintaining a negative energy balance. TRF can be implemented intentionally with CR, or TRF might induce CR simply because of the time restriction. This review focuses on summarizing our current knowledge on how TRF and continuous CR affect gut peptides that influence satiety. Based on peer-reviewed studies, in response to CR there is an increase in the orexigenic hormone ghrelin and a reduction in fasting leptin and insulin. There is likely a reduction in glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK), albeit the evidence for this is weak. After TRF, unlike CR, fasting ghrelin decreased in some TRF studies, whereas it showed no change in several others. Further, a reduction in fasting leptin, insulin, and GLP-1 has been observed. In conclusion, when other determinants of food intake are held equal, the peripheral satiety systems appear to be somewhat similarly affected by CR and TRF with regard to leptin, insulin, and GLP-1. But unlike CR, TRF did not appear to robustly increase ghrelin, suggesting different influences on appetite with a potential decrease of hunger after TRF when compared with CR. However, there are several established and novel gut peptides that have not been measured within the context of CR and TRF, and studies that have evaluated effects of TRF are often short-term, with nonuniform study designs and highly varying temporal eating patterns. More evidence and studies addressing these aspects are needed to draw definitive conclusions.
• Artegoitia, V. M., Krishnan, S., Bonnel, E. L., Stephensen, C. B., Keim, N. L., & Newman, J. W. (2021). Healthy eating index patterns in adults by sex and age predict cardiometabolic risk factors in a cross-sectional study. BMC nutrition, 7(1), 30.
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  Associations between diet and cardiometabolic disease (CMD) risk may vary in men and women owing to sex differences in eating habits and physiology. The current secondary analysis sought to determine the ability of sex differences in dietary patterns to discriminate groups with or without CMD risk factors (CMDrf) in the adult population and if this was influenced by age.
• Kim, T., Xie, Y., Li, Q., Artegoitia, V. M., Lebrilla, C. B., Keim, N. L., Adams, S. H., & Krishnan, S. (2021). Diet affects glycosylation of serum proteins in women at risk for cardiometabolic disease. European journal of nutrition, 60(7), 3727-3741.
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  Glycoproteomics deals with glycoproteins that are formed by post-translational modification when sugars (like fucose and sialic acid) are attached to protein. Glycosylation of proteins influences function, but whether glycosylation is altered by diet is unknown.
• Krishnan, S., & Krishnan, G. P. (2021). N-Glycosylation Network Construction and Analysis to Modify Glycans on the Spike (S) Glycoprotein of SARS-CoV-2. Frontiers in bioinformatics, 1, 667012.
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  The N-glycan structure and composition of the spike (S) protein of SARS-CoV-2 are pertinent to vaccine development and efficacy. We reconstructed the glycosylation network based on previously published mass spectrometry data using GNAT, a glycosylation network analysis tool. Our compilation of the network tool had 26 glycosyltransferase and glucosidase enzymes and could infer the pathway of glycosylation machinery based on glycans in the virus spike protein. Once the glycan biosynthesis pathway was generated, we simulated the effect of blocking specific enzymes-swainsonine or deoxynojirimycin for blocking mannosidase-II and indolizidine for blocking alpha-1,6-fucosyltransferase-to see how they would affect the biosynthesis network and the glycans that were synthesized. The N-glycan biosynthesis network of SARS-CoV-2 spike protein shows an elaborate enzymatic pathway with several intermediate glycans, along with the ones identified by mass spectrometric studies. Of the 26 enzymes, the following were involved-Man-Ia, MGAT1, MGAT2, MGAT4, MGAT5, B3GalT, B4GalT, Man-II, SiaT, ST3GalI, ST3GalVI, and FucT8. Blocking specific enzymes resulted in a substantially modified glycan profile of SARS-CoV-2. Variations in the final N-glycan profile of the virus, given its site-specific microheterogeneity, are factors in the host response to the infection, vaccines, and antibodies. Heterogeneity in the N-glycan profile of the spike (S) protein and its potential effect on vaccine efficacy or adverse reactions to the vaccines remain unexplored. Here, we provide all the resources we generated-the glycans in the glycoCT xml format and the biosynthesis network for future work.
• Krishnan, S., Adams, S. H., Witbracht, M. G., Woodhouse, L. R., Piccolo, B. D., Thomas, A. P., Souza, E. C., Horn, W. F., Gertz, E. R., Van Loan, M. D., & Keim, N. L. (2021). Weight Loss, but Not Dairy Composition of Diet, Moderately Affects Satiety and Postprandial Gut Hormone Patterns in Adults. The Journal of nutrition, 151(1), 245-254.
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  Inclusion of dairy in diet patterns has been shown to have mixed effects on weight loss. A prevailing hypothesis is that dairy improves weight loss by influencing endocrine systems associated with satiety and food intake regulation.
• Krishnan, S., O'Connor, L. E., Wang, Y., Gertz, E. R., Campbell, W. W., & Bennett, B. J. (2021). Adopting a Mediterranean-style eating pattern with low, but not moderate, unprocessed, lean red meat intake reduces fasting serum trimethylamine N-oxide (TMAO) in adults who are overweight or obese. The British journal of nutrition, 128(9), 1-21.
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  A Mediterranean-style eating pattern (MED-EP) may include moderate red meat intake. However, it is unknown if the pro-atherogenic metabolite trimethylamine N-oxide (TMAO) is affected by the amount of red meat consumed with a MED-EP. The results presented are from a secondary, retrospective objective of an investigator-blinded, randomized, crossover, controlled feeding trial (two 5-wk interventions separated by a 4-wk washout) to determine if a MED-EP with 200g unprocessed lean red meat/wk (MED-CONTROL) reduces circulating TMAO concentrations compared to a MED-EP with 500g unprocessed lean red meat/wk (MED-RED). Participants were 27 women and 12 men (n=39 total) who were either overweight or obese (BMI: 30.5 ± 0.3 kg/m2 mean ± SEM). Serum samples were obtained following an overnight fast both before (pre) and after (post) each intervention. Fasting serum TMAO, choline, carnitine, and betaine concentrations were measured using a targeted Liquid chromatography-mass spectrometry. Data were analyzed to assess if (a) TMAO and related metabolites differed by intervention, and (b) if changes in TMAO were associated with changes in Framingham 10-year risk score. Serum TMAO was lower post-intervention following MED-CONTROL compared to MED-RED intervention (post-MED-CONTROL 3.1 ± 0.2 µM vs. post-MED-RED 5.0 ± 0.5 µM, p
• Krishnan, S., & Ramyaa, R. (2020). When two heads are better than one: nutritional epidemiology meets machine learning. The American journal of clinical nutrition, 111(6), 1124-1126.
• Krishnan, S., Lee, F., Burnett, D. J., Kan, A., Bonnel, E. L., Allen, L. H., Adams, S. H., & Keim, N. L. (2020). Challenges in Designing and Delivering Diets and Assessing Adherence: A Randomized Controlled Trial Evaluating the 2010 Dietary Guidelines for Americans. Current developments in nutrition, 4(3), nzaa022.
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  Controlled-feeding trials are challenging to design and administer in a free-living setting. There is a need to share methods and best practices for diet design, delivery, and standard adherence metrics.
• Ramyaa, R., Hosseini, O., Krishnan, G. P., & Krishnan, S. (2019). Phenotyping Women Based on Dietary Macronutrients, Physical Activity, and Body Weight Using Machine Learning Tools. Nutrients, 11(7).
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  Nutritional phenotyping can help achieve personalized nutrition, and machine learning tools may offer novel means to achieve phenotyping. The primary aim of this study was to use energy balance components, namely input (dietary energy intake and macronutrient composition) and output (physical activity) to predict energy stores (body weight) as a way to evaluate their ability to identify potential phenotypes based on these parameters. From the Women's Health Initiative Observational Study (WHI OS), carbohydrates, proteins, fats, fibers, sugars, and physical activity variables, namely energy expended from mild, moderate, and vigorous intensity activity, were used to predict current body weight (both as body weight in kilograms and as a body mass index (BMI) category). Several machine learning tools were used for this prediction. Finally, cluster analysis was used to identify putative phenotypes. For the numerical predictions, the support vector machine (SVM), neural network, and k-nearest neighbor (kNN) algorithms performed modestly, with mean approximate errors (MAEs) of 6.70 kg, 6.98 kg, and 6.90 kg, respectively. For categorical prediction, SVM performed the best (54.5% accuracy), followed closely by the bagged tree ensemble and kNN algorithms. K-means cluster analysis improved prediction using numerical data, identified 10 clusters suggestive of phenotypes, with a minimum MAE of ~1.1 kg. A classifier was used to phenotype subjects into the identified clusters, with MAEs
• Forester, S. M., Widaman, A. M., Krishnan, S., Witbracht, M. G., Horn, W. F., Laugero, K. D., & Keim, N. L. (2018). A Clear Difference Emerges in Hormone Patterns Following a Standard Midday Meal in Young Women Who Regularly Eat or Skip Breakfast. The Journal of nutrition, 148(5), 685-692.
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  Multiple hormones are involved in the regulation of food intake and glucose metabolism. Past intervention studies showed a benefit of eating breakfast on satiety, but this was possibly confounded by the disruption of habitual meal patterns.
• Krishnan, S., Adams, S. H., Allen, L. H., Laugero, K. D., Newman, J. W., Stephensen, C. B., Burnett, D. J., Witbracht, M., Welch, L. C., Que, E. S., & Keim, N. L. (2018). A randomized controlled-feeding trial based on the Dietary Guidelines for Americans on cardiometabolic health indexes. The American journal of clinical nutrition, 108(2), 266-278.
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  The 2010 Dietary Guidelines for Americans (DGA) recommend nutrient needs be met by increasing fruit, vegetable, and whole-grain intake with the use of low-fat or fat-free dairy products and by reducing sodium, solid fats, and added sugars. However, the DGA, as a dietary pattern, have not been tested in an intervention trial.
• Krishnan, S., Agrawal, K., Tryon, R. R., Welch, L. C., Horn, W. F., Newman, J. W., & Keim, N. L. (2018). Structural equation modeling of food craving across the menstrual cycle using behavioral, neuroendocrine, and metabolic factors. Physiology & behavior, 195, 28-36.
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  To identify associations between circulating endocannabinoids and craving during the luteal phase of the menstrual cycle. This report is a secondary analysis of a trial registered in clinicaltrials.gov as NCT01407692.
• Mangrola, D., Cox, C., Furman, A. S., Krishnan, S., & Karakas, S. E. (2018). SELF BLOOD GLUCOSE MONITORING UNDERESTIMATES HYPERGLYCEMIA AND HYPOGLYCEMIA AS COMPARED TO CONTINUOUS GLUCOSE MONITORING IN TYPE 1 AND TYPE 2 DIABETES. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 24(1), 47-52.
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  When glucose records from self blood glucose monitoring (SBGM) do not reflect estimated average glucose from glycosylated hemoglobin (HgBA1) or when patients' clinical symptoms are not explained by their SBGM records, clinical management of diabetes becomes a challenge. Our objective was to determine the magnitude of differences in glucose values reported by SBGM versus those documented by continuous glucose monitoring (CGM).
• Mangrola, D., Cox, C., Furman, A., Krishnan, S., & Karakas, S. (2018). Self blood glucose monitoring underestimates hyperglycemia and hypoglycemia as compared to continuous glucose monitoring in type 1 and type 2 diabetes. Endocrine Practice, 24(1). doi:10.4158/EP-2017-0032
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  Objective: When glucose records from self blood glucose monitoring (SBGM) do not reflect estimated average glucose from glycosylated hemoglobin (HgBA1) or when patients' clinical symptoms are not explained by their SBGM records, clinical management of diabetes becomes a challenge. Our objective was to determine the magnitude of differences in glucose values reported by SBGM versus those documented by continuous glucose monitoring (CGM). Methods: The CGM was conducted by a clinical diabetes educator (CDE)/registered nurse by the clinic protocol, using the Medtronic iPRO2TM system. Patients continued SBGM and managed their diabetes without any change. Data from 4 full days were obtained, and relevant clinical information was recorded. De-identified data sets were provided to the investigators. Results: Data from 61 patients, 27 with type 1 diabetes (T1DM) and 34 with T2DM were analyzed. The lowest, highest, and average glucose recorded by SBGM were compared to the corresponding values from CGM. The lowest glucose values reported by SBGM were approxi-mately 25 mg/dL higher in both T1DM (P = .0232) and T2DM (P = .0003). The highest glucose values by SBGM were approximately 30 mg/dL lower in T1DM (P = .0005) and 55 mg/dL lower in T2DM (P
• Davis, J. C., Lewis, Z. T., Krishnan, S., Bernstein, R. M., Moore, S. E., Prentice, A. M., Mills, D. A., Lebrilla, C. B., & Zivkovic, A. M. (2017). Growth and Morbidity of Gambian Infants are Influenced by Maternal Milk Oligosaccharides and Infant Gut Microbiota. Scientific reports, 7, 40466.
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  Human milk oligosaccharides (HMOs) play an important role in the health of an infant as substrate for beneficial gut bacteria. Little is known about the effects of HMO composition and its changes on the morbidity and growth outcomes of infants living in areas with high infection rates. Mother's HMO composition and infant gut microbiota from 33 Gambian mother/infant pairs at 4, 16, and 20 weeks postpartum were analyzed for relationships between HMOs, microbiota, and infant morbidity and growth. The data indicate that lacto-N-fucopentaose I was associated with decreased infant morbidity, and 3'-sialyllactose was found to be a good indicator of infant weight-for-age. Because HMOs, gut microbiota, and infant health are interrelated, the relationship between infant health and their microbiome were analyzed. While bifidobacteria were the dominant genus in the infant gut overall, Dialister and Prevotella were negatively correlated with morbidity, and Bacteroides was increased in infants with abnormal calprotectin. Mothers nursing in the wet season (July to October) produced significantly less oligosaccharides compared to those nursing in the dry season (November to June). These results suggest that specific types and structures of HMOs are sensitive to environmental conditions, protective of morbidity, predictive of growth, and correlated with specific microbiota.
• Hawkins, K. R., Krishnan, S., Ringos, L., Garcia, V., & Cooper, J. A. (2017). Running Performance With Nutritive and Nonnutritive Sweetened Mouth Rinses. International journal of sports physiology and performance, 12(8), 1105-1110.
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  Using mouth rinse (MR) with carbohydrate during exercise has been shown to act as an ergogenic aid.
• Krishnan, S., Shimoda, M., Sacchi, R., Kailemia, M. J., Luxardi, G., Kaysen, G. A., Parikh, A. N., Ngassam, V. N., Johansen, K., Chertow, G. M., Grimes, B., Smilowitz, J. T., Maverakis, E., Lebrilla, C. B., & Zivkovic, A. M. (2017). HDL Glycoprotein Composition and Site-Specific Glycosylation Differentiates Between Clinical Groups and Affects IL-6 Secretion in Lipopolysaccharide-Stimulated Monocytes. Scientific reports, 7, 43728.
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  The goal of this pilot study was to determine whether HDL glycoprotein composition affects HDL's immunomodulatory function. HDL were purified from healthy controls (n = 13), subjects with metabolic syndrome (MetS) (n = 13), and diabetic hemodialysis (HD) patients (n = 24). Concentrations of HDL-bound serum amyloid A (SAA), lipopolysaccharide binding protein (LBP), apolipoprotein A-I (ApoA-I), apolipoprotein C-III (ApoC-III), α-1-antitrypsin (A1AT), and α-2-HS-glycoprotein (A2HSG); and the site-specific glycovariations of ApoC-III, A1AT, and A2HSG were measured. Secretion of interleukin 6 (IL-6) in lipopolysaccharide-stimulated monocytes was used as a prototypical assay of HDL's immunomodulatory capacity. HDL from HD patients were enriched in SAA, LBP, ApoC-III, di-sialylated ApoC-III (ApoC-III) and desialylated A2HSG. HDL that increased IL-6 secretion were enriched in ApoC-III, di-sialylated glycans at multiple A1AT glycosylation sites and desialylated A2HSG, and depleted in mono-sialylated ApoC-III (ApoC-III). Subgroup analysis on HD patients who experienced an infectious hospitalization event within 60 days (HD+) (n = 12), vs. those with no event (HD-) (n = 12) showed that HDL from HD+ patients were enriched in SAA but had lower levels of sialylation across glycoproteins. Our results demonstrate that HDL glycoprotein composition, including the site-specific glycosylation, differentiate between clinical groups, correlate with HDL's immunomodulatory capacity, and may be predictive of HDL's ability to protect from infection.
• Krishnan, S., Steffen, L. M., Paton, C. M., & Cooper, J. A. (2017). Impact of dietary fat composition on prediabetes: a 12-year follow-up study. Public health nutrition, 20(9), 1617-1626.
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  Dietary fatty acid composition likely affects prediabetic conditions such as isolated impaired fasting glucose (IFG) or impaired glucose tolerance (IGT); however, this risk has not been evaluated in a large population nor has it been followed prospectively.
• Krishnan, S., Tryon, R., Horn, W., Welch, L., & Keim, N. (2016). Estradiol, SHBG and leptin interplay with food craving and intake across the menstrual cycle. Physiology and Behavior, 165. doi:10.1016/j.physbeh.2016.08.010
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  Objective To understand the association between ovarian hormones, non-acute satiety hormones and craving calorie dense foods in the luteal phase. Methods 17 premenopausal women, mean age 23.2 y, mean BMI 22.4 kg/m2 with regular menstrual cycles were studied during late follicular (FP) and luteal phases (LP). Estradiol, progesterone, DHEAS, SHBG, insulin and leptin, were measured in fasting samples. The validated Food Craving Inventory was used to record the types of foods volunteers habitually ate – rich in fat, carbohydrate or sweet taste, as well as craved during the LP of their menstrual cycle. Results Estradiol was inversely associated with leptin in FP (r = − 0.62, p = 0.01). Leptin was inversely associated with habitual intake of sweet foods, in both phases (FP: r = − 0.64, p = 0.01; LP: r = − 0.63, p = 0.01). SHBG in LP was positively associated with craving sweet and carbohydrate rich foods. Hierarchical cluster analysis revealed two groups of women, one with high estradiol, high estradiol/leptin ratio, high sweet and carbohydrate cravings (p < 0.05); the other group had lower estradiol, lower estradiol/leptin ratio, and reported less craving. Conclusions The estradiol-leptin axis may be a determinant of luteal phase craving and habitual food intake in menstruating women. Clinical Trial Registration Number: NCT01407692
• Stevenson, J., Krishnan, S., Inigo, M., Stamatikos, A., Gonzales, J., & Cooper, J. (2016). Echinacea-Based Dietary Supplement Does Not Increase Maximal Aerobic Capacity in Endurance-Trained Men and Women. Journal of Dietary Supplements, 13(3). doi:10.3109/19390211.2015.1036189
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  To determine if an echinacea-based dietary supplement (EBS) provided at two different doses (a regular dose (RD), 8,000 mg/day, vs. a double dose (DD), 16,000 mg/day) would increase erythropoietin (EPO) and other blood markers involved in improving aerobic capacity and maximal oxygen consumption (VO2max) in endurance-trained men. Secondly, to determine if any sex differences exist between male and female endurance-trained athletes. Methods: Forty-five endurance athletes completed three visits during a 35-day intervention. Participants were randomized into placebo (PLA; n = 8 men, n = 7 women), RD of EBS (n = 7 men, n = 8 women), or DD of EBS (n = 15 men) for the 35-day intervention period. At baseline, weight, body composition, and VO2max were measured. Blood was drawn to measure EPO, ferritin, red blood cells, white blood cells, hemoglobin, and hematocrit. At the mid-intervention visit, blood was collected. At the post-intervention visit, all measurements from the baseline visit were obtained once again. Results: There was a significant increase in VO2max for endurance-trained men in PLA (increase of 2.8 ± 1.5 ml kg-1 min-1, p =.01) and RD of EBS (increase of 2.6 ± 1.8 ml kg-1 min-1, p =.04), but not in DD of EBS (p =.96). Importantly, there was no difference in the change in VO2max between PLA and RD of EBS. For endurance-trained women, VO2max did not change in either treatment (PLA:-0.7 ± 1.7 ml kg-1 min-1, p =.31; RD of EBS:-0.2 ± 2.4 ml kg-1 min-1, p =.80). There were no significant changes in any blood parameter across visits for any treatment group. Conclusions: This EBS should not be recommended as a means to improve performance in endurance athletes.
• Krishnan, S., Huang, J., Lee, H., Guerrero, A., Berglund, L., Anuurad, E., Lebrilla, C., & Zivkovic, A. (2015). Combined High-Density Lipoprotein Proteomic and Glycomic Profiles in Patients at Risk for Coronary Artery Disease. Journal of Proteome Research, 14(12). doi:10.1021/acs.jproteome.5b00730
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  Objectives: To test whether recently developed methods for comprehensive profiling of the high-density lipoprotein (HDL) glycome combined with the HDL proteome can distinguish individuals with coronary artery disease (CAD) from those without. Methods: Twenty subjects at risk for CAD, who underwent diagnostic coronary arteriography, were analyzed. Ten subjects had CAD, and ten did not. HDL was extracted from fasting plasma samples by ultracentrifugation, followed by shotgun proteomic, glycomic, and ganglioside analyses using LC-MS. CAD vs non-CAD subjects' data were compared using univariate and multivariate statistics. Results: Principal components analysis showed a clear separation of CAD and non-CAD subjects, confirming that combined HDL proteomic and glycomic profiles distinguished at-risk subjects with atherosclerosis from those without. CAD patients had lower HDL apolipoprotein content (specifically ApoA-I, A-II, and E, p < 0.05), and lower serum amyloid A2 (SAA2, p = 0.020) and SAA4 (p = 0.007) but higher sialylated glycans (p < 0.05). Conclusion: Combined proteomic and glycomic profiling of isolated HDL was tested as a novel analytical approach for developing biomarkers of disease. In this pilot study we found that HDL proteome and glycome distinguished between individuals who had CAD from those who did not within a group of individuals equally at risk for heart disease.
• Krishnan, S., Tokar, T., Boylan, M., Griffin, K., Feng, D., Mcmurry, L., Esperat, C., & Cooper, J. (2015). Zumba® dance improves health in overweight/obese or type 2 diabetic women. American Journal of Health Behavior, 39(1). doi:10.5993/AJHB.39.1.12
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  Objective: To evaluate the feasibility and health improvements from a Zumba® intervention in overweight/obese women. Methods: Twenty-eight (14 type 2 diabetic and 14 non-diabetic) overweight/obese women (BMI: 37.3±1.5 kg/m2 ) 50.8±1.8 y of age, completed a 16-week intervention attending Zumba® dance classes 3 days/week, 60 minutes/class. We measured aerobic fitness, body weight, body fat %, and motivation to exercise before and after the study. Results: Intrinsic motivation to exercise (p < .05) and aerobic fitness (1.01 ± 0.40 mL/kg/min, p < .05) improved, and the participants lost body weight (-1.05 ± 0.55kg, p < .05) and body fat% (-1.2 ± 0.6%, p < .01). Conclusion: The Zumba® intervention improved health and physical fitness in women.
• Krishnan, S., Gustafson, M., Campbell, C., Gaikwad, N., & Keim, N. (2014). Association between circulating endogenous androgens and insulin sensitivity changes with exercise training in midlife women. Menopause, 21(9). doi:10.1097/GME.0000000000000198
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  Objective: Aging induces a shift in circulating hormones in women, accompanied by weight gain during the late reproductive, menopausal transition, and postmenopausal years. Exercise has been shown to counter weight gain; however, it might increase circulating androgens. A 6-month aerobic and resistance training exercise regimen was implemented to examine interrelationships between circulating sex hormones, body composition, aerobic capacity, insulin sensitivity, and insulin resistance. Methods: Twenty-eight women, aged 42 to 52 years, completed the 6-month intervention study. They were randomly assigned to either a control (CON; n = 10) group - and maintained their sedentary lifestyle - or an exercise intervention (EXE; n = 18) group. The exercise intervention consisted of combined aerobic and resistance workouts scheduled 6 days/week for 60 minutes/day. Body weight, composition, VO2 peak, plasma insulin, glucose, lipid profile, estradiol, testosterone, progesterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate (DHEAS) were measured at baseline and on month 6. Insulin sensitivity was estimated using the insulin sensitivity index and the quantitative insulin sensitivity check index, whereas insulin resistance was estimated using the homeostatic model for insulin resistance. Results: There was a trend toward increased DHEAS in both groups (P < 0.1), but not as a function of the intervention. Insulin sensitivity index increased in the EXE group compared with the CON group (P < 0.01). Multiple linear regression indicated that, at 6 months, DHEAS was a negative contributor to insulin sensitivity in the EXE group, but not in the CON group. Conclusions: In midlife women, an increase in circulating DHEAS, such as that previously reported during the menopausal transition, is associated with higher insulin resistance, but exercise can mitigate this risk by improving insulin sensitivity, thereby countering the effects of DHEAS. © 2014 by The North American Menopause Society.
• Stevenson, J., Krishnan, S., Stoner, M., Goktas, Z., & Cooper, J. (2013). Effects of exercise during the holiday season on changes in body weight, body composition and blood pressure. European Journal of Clinical Nutrition, 67(9). doi:10.1038/ejcn.2013.98
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  Background/objectives: Identifying critical periods of greater weight gain could provide useful information to combat the obesity epidemic. We tested whether body weight (BW), body fat percentage (BF%) and blood pressure (BP) changed during the holiday season (thanksgiving to new year's day) and the impact of regular exercise on these parameters. Subjects/methods: A total of 48 males and 100 females (age 18-65 years) with a mean body mass index of 25.1±0.5 kg/m2 were evaluated in mid-November (visit 1) and early January (visit 2; across 57±0.5 days). Anthropometric data, BF%, BP and self-reported exercise were recorded. Results: Participants showed significant increases in BW (0.78±0.1 kg, P
• Krishnan, S., Newman, J., Hembrooke, T., & Keim, N. (2012). Variation in metabolic responses to meal challenges differing in glycemic index in healthy women: Is it meaningful?. Nutrition and Metabolism, 9. doi:10.1186/1743-7075-9-26
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  Background: Established clinical tests are commonly used in disease diagnosis, but tools that enhance identification of metabolic dysfunctions are needed. This study was conducted to identify typical and atypical metabolite temporal patterns in response to paired meal challenge tests. Design. Metabolic responses to high and low glycemic index (GI) meals were tested in 24 healthy pre-menopausal women, aged 20-50 y, with BMI of 25-30 kg/m 2 using a cross-over design. On test days, blood glucose, insulin, leptin and non-esterified fatty acids were measured after an overnight fasting, and for 8 h following test meal consumption. The data were range scaled, and multivariate statistics were used to assess the presence of distinct response groups to the meal challenge tests. Results: As expected, participants showed higher circulating glucose and insulin in response to the high GI compared to the low GI meal challenge. However, using range-scaling and Principal Component Analysis, three distinct groups were identified based on differential responses to the paired challenges. Members of the most populated group (n = 18) displayed little deviation from the expected response to the two meal challenges. Two minor groups (n = 3/group) with distinct responses were observed, one suggestive of sub-clinical insulin resistance, and the other suggestive of hyperleptinemia. Conclusions: The differential responses of glucose, insulin and leptin to low and high glycemic test meals revealed three response groups. Dietary intervention studies traditionally evaluate group responses, and aim to identify the overall effect in the population studied. In contrast, our study analyzed the variance in the meal challenge responses, using an integrated physiological approach, rather than a reductionist approach. This phenotyping approach may be useful for detecting subclinical metabolic dysfunctions, and it could contribute to improved personalized nutrition management. This study is registered in ClinicalTrials.gov, record #200210295. © 2012 Krishnan et al; licensee BioMed Central Ltd.